SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome.

Abstract

Acetylation is increasingly recognized as an important metabolic regulatory posttranslational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. Mice lacking SIRT3 (SIRT3KO) placed on a HFD show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type (WT) mice. The lipogenic enzyme stearoyl-CoA desaturase 1 is highly induced in SIRT3KO mice, and its deletion rescues both WT and SIRT3KO mice from HFD-induced hepatic steatosis and insulin resistance. We further identify a single nucleotide polymorphism in the human SIRT3 gene that is suggestive of a genetic association with the metabolic syndrome. This polymorphism encodes a point mutation in the SIRT3 protein, which reduces its overall enzymatic efficiency. Our findings show that loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome.

• Authors: Matthew D Hirschey, Tadahiro Shimazu, Enxuan Jing, Carrie A Grueter, Amy M Collins, Bradley Aouizerat, Alena Stančáková, Eric Goetzman, Maggie M Lam, Bjoern Schwer, Robert D Stevens, Michael J Muehlbauer, Sanjay Kakar, Nathan M Bass, Johanna Kuusisto, Markku Laakso, Frederick W Alt, Christopher B Newgard, Robert V Farese Jr, C Ronald Kahn, Eric Verdin
• Journal: Molecular cell (Mol Cell) Vol. 44 Issue 2 Pg. 177-90 (Oct 21 2011) ISSN: 1097-4164 [Electronic] United States
• PMID: 21856199 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Mitochondrial Proteins
• Sirtuin 3

Topics

• Acetylation
• Animals
• Diet, High-Fat
• Humans
• Metabolic Syndrome (genetics, metabolism)
• Mice
• Mice, Knockout
• Mitochondrial Proteins (metabolism)
• Models, Biological
• Sirtuin 3 (genetics, metabolism)